Danger ahead: the growing threat of fungal disease and antifungal resistance

Often associated with relatively minor irritations, such as bread mould or athlete’s foot, fungi also have a much darker side. Life-threatening fungal infections affect 6.5 million people worldwide each year and cause an estimated 2.5 million deaths^​1​.

“More people die from fungal disease than they do from tuberculosis and malaria combined,” says Lewis White, professor of medical mycology at Cardiff University School of Medicine and head of the Public Health Wales Mycology Reference Laboratory.

What’s more, the threat of fungal disease is on the rise in England. In June 2026, the UK Health Security Agency reported that between 2024 and 2025, the rate of bloodstream infections caused by yeasts, including Candida albicans, increased by 6%, from 3.9 to 4.1 per 100,000 people. The number of laboratory reports also increased by 35%, from 1,786 reports to 2,408 reports^​2​.

This local and global increase in fungal infections goes hand in hand with a rise in resistance to available antifungal medicines, much like what has happened with bacteria and antibiotics. This is partially owed to heavy agricultural fungicide use, which is breeding resistant strains in the environment. Another factor is the growing numbers of immunocompromised patients requiring prolonged or repeated antifungal treatments, which can create more opportunities for resistant strains to emerge in the body.

Wariness is, therefore, not unwarranted. The antifungal arsenal is small, with medicines belonging to one of only three major classes: azoles, echinocandins and polyenes^​3​. While most fungal infections still respond to frontline drugs in the UK, growing resistance threatens to undercut their potency.

Many experts are taking note of this increasing threat. In 2022, the World Health Organization (WHO) established the Fungal Priority Pathogen List (FPPL), while in June 2026, the WHO issued recommendations for strengthening responses to fungal disease and antifungal resistance. These recommendations included raising awareness, expanding access to antifungal medicines and building laboratory networks to monitor fungal disease and antifungal resistance^​4​.

To stay a step ahead, many pharmacists are incorporating antifungal stewardship into their antimicrobial stewardship programmes. The pharmaceutical industry is also developing antifungals with novel mechanisms of action, and researchers are devising more efficient methods to identify fungal infections, as well as cases of resistance. These actions must be coordinated across governmental, clinical and agricultural domains, in a so-called ‘One Health approach’ that aims to preserve the health of crops, animals and humans.

“We can’t simply stop using agricultural fungicides, because this would cause a famine, which would probably kill more people than fungal disease,” says Stephen Hughes, pharmacist and antimicrobial stewardship lead at Chelsea and Westminster NHS Foundation Trust. “We must balance protecting our food supply, while ensuring agricultural use doesn’t drive resistance to human medicines.”

The rise and rise of fungal disease

Of the several million species of fungi on Earth, only a minority make humans sick. Most can be easily dispatched by our immune systems, whereas others, such as Candida albicans, are part of a healthy human microbiome^​5​.

However, life-threatening fungal infections – caused by the likes of the Candida, Aspergillus, Pneumocystis, and Cryptococcal species – have become more common in recent years. This is in part because advances in medicine mean that more people are living with weakened immune systems, owing to underlying illness, older age or treatments such as chemotherapy and corticosteroids. People with weakened immune systems are more susceptible to fungal infections, either acquired from the environment or caused by fungi that normally live in or on the body.

Owing to a lack of reliable tests, fungal diseases are notoriously difficult to diagnose. Yet, emerging estimates point to a significant disease burden within the UK. In Wales, these types of infections comprise up to 30 cases per 100,000 people annually^​6​, while in England, cases of infection by the new and deadly yeast Candidozyma auris have also increased over the past five years^​7​.

Owing to this difficulty in diagnosis, fungal infections are often not identified until they are already well-established within the bloodstream or internal organs, by which point they are more likely to lead to death. For example, invasive Aspergillus fumigatus infection has a 20% or higher mortality at six months^​1,8​, while Candida infections show over 30% mortality at 30 days for critically ill patients^​9,10​.

Candidozyma auris, which has a reported mortality of 30–60%^​11​, thrives in hospital settings. It colonises skin, sheds onto equipment, clings to plastic and surfaces and withstands standard hospital cleaning protocols. In England, five Candidozyma auris outbreaks were recorded in hospitals between April 2025 and September 2025, which is the most recent six-month reporting period^​7​.

While Candidozyma auris strains in the UK remain treatable, some found outside of the UK have started showing resistance to all antifungals^​12​. The cause of this resistance remains unknown.

Increasing resistance

Other antifungal resistant infections have much clearer origins. Azole resistance by Aspergillus fumigatus has risen as an unintended consequence of agricultural fungicide use.

Aspergillus fumigatus is a common mould that thrives in soil and compost, releasing spores that become airborne. In soil, Aspergillus fumigatus can be exposed to azole fungicides, which are commonly used on UK crops, and has thus adapted to develop resistance. Azole-resistant Aspergillus fumigatus is now widespread in the UK, which is found in garden soils^​13​ and the air. The results of a study published in 2023 estimate that people are exposed to airborne azole-resistant spores on 21 days each year^​14​.

A role for the environment was first suspected when azole-resistant Aspergillus fumigatus infections were identified in people with no previous exposure to medical azoles^​15​. This suggested that they had inhaled spores that were already resistant. This explanation was supported when azole-resistant species were found in the soils of azole-treated fields but not in untreated urban areas^​16​.

This has created a dangerous situation for critically ill people with invasive Aspergillus fumigatus infections. Resistance to the azole voriconazole has been associated with 100% mortality at 90 days^​17​. In the Netherlands, heavy azole fungicide use in flower bulb cultivation has incurred such a high rate of azole-resistant Aspergillus fumigatus infection that the standard treatment now combines an azole agent with an echinocandin^​18​.

Antifungal resistance can also emerge within a patient during treatment — for example, in immunosuppressed patients receiving prolonged fluconazole therapy^​19​. However, resistance generally spreads less readily between fungi than it does between bacteria. This is because fungi — as eukaryotes — do not transfer genetic material between themselves in the way that prokaryotic bacteria can.

Pharmacists in antimicrobial resistance (AMR) services keep the possibility of antifungal resistance in mind, particularly in hospitals that serve immunocompromised patients. The goals of an AMR programme — which is to improve outcomes of patients with infections by getting them the right treatment, at the right dose, at the right time — remain the same, for fungi or otherwise.

“Antifungal resistance should not be seen as a lesser concern than antibacterial resistance,” says Amira Guirguis, chief scientist at the Royal College of Pharmacy. “It is part of the wider AMR challenge and requires the same focus on prevention, responsible prescribing, rapid diagnosis, surveillance and research.”

Charlotte Gurr

Antifungals: old and new

Any antifungal resistance erodes the options for severely ill patients. “Even when the overall proportion of resistant infections remains relatively modest, the clinical consequences for individual patients can be serious,” says Guirguis.

The WHO describes antifungal resistance as “one of global health’s most underestimated and neglected threats”, highlighting the urgent need to expand the shortlist of antifungal agents.

The three classes of available antifungals work through different mechanisms. Azoles and polyenes both target ergosterol, which is a lipid that is an essential component of the fungal cell membrane. Azoles target a key enzyme for ergosterol production, while polyenes, such as amphotericin B, bind directly to ergosterol and damage the membrane. The third class, echinocandins, target the fungal cell wall instead, inhibiting the production of beta-D-glucan, which is an important structural component.

Fungi have acquired resistance to these drugs through multiple mechanisms. Azole resistance is commonly conferred through mutations to the CYP51A gene, which encodes the ergosterol-making enzyme, weakening the interaction between azoles and its target. Other mechanisms weaken antifungal effects by increasing production of the treatment’s target, or by using efflux pumps — proteins that transport antifungal drugs out of the fungal cell — to remove antifungals^​5​.

To combat this increasing resistance, drugs with novel mechanisms of action are under development. In 2021, a triterpenoid antifungal called ibrexafungerp (BREXAFEMME; Scynexis, Inc) was approved for vaginal Candida infections in the United States. Ibrexafungerp targets the same glucan-making enzyme as echinocandins but binds to a different site and can be taken orally^​20​. It is now in a phase III study of severe fungal infections^​21​.

“This is a genuine game changer,” says Hughes, referring to the oral bioavailability, which will allow outpatient treatment of fungal infections.

Two other new antifungal classes are also in the pipeline. Fosmanogepix (Basilea) inhibits an enzyme needed to anchor mannoproteins to the fungal cell surface, disrupting processes including adhesion to host tissue. It is now also in a phase III trials for invasive mould infections^​22​ and candidiasis^​23​.

An orotomide compound called olorofim (F2G) targets dihydroorotate dehydrogenase (DHODH), an enzyme needed in DNA and RNA production in fungi. After success in an open-label phase IIb trial^​24​, a phase III trial in patients with invasive Aspergillus infection is now underway^​25​.

New ideas are also emerging for polyene antifungals. In July 2026, researchers from Imperial College London and the University of Manchester reported enzymatic pathways that attach sugars to polyene compounds. Using these pathways, they created a new family of polyene antifungals that showed high potency and low toxicity in mouse models of invasive aspergillosis^​26​.

Working together for One Health

However, discovering new compounds will not be enough on its own. While olorofim is advancing through clinical trials, a fungicide with the same mechanism of action has been approved for agricultural use in the United States.

“Even before we’ve got a clinic with [olorofim], it’s potentially being compromised by new agricultural practices,” says White, who is involved in the olorofim clinical trials.

This conundrum highlights the need for a ‘One Health approach’. In September 2025, a Fungal One Health and Antimicrobial Resistance Network (F1AMR) launched, which included a roundtable discussion in the House of Lords. It addressed these issues with a group of experts and stakeholders from across medical, agricultural, environmental, basic science, pharmaceutical and government sectors.

This prompted three recommendations for a coordinated response to the threat of antifungal resistance in the UK:

1. A cross-government body tasked with centralised decision-making for fungicide use in agriculture and antifungal resistance clinical policies;
2. Mandatory and systematic surveillance of antifungal resistance in the environment and in clinical hotspots;
3. Agricultural fungicide authorisations that include a risk assessment for antifungal resistance^​3​.

Surveillance is crucial for understanding the scale of antifungal resistance but, as touched upon earlier, counting cases of fungal disease is difficult. Tests for fungal infection begin with patient biospecimens such as blood or sputum. If a fungus is successfully grown, the culture can undergo antifungal susceptibility testing to identify those that are resistant.

This is a time-consuming process beyond the capabilities of most diagnostic labs. Even if a fungus is successfully isolated from a patient, this often falls short of a diagnosis because some fungi are opportunistic pathogens. Diagnosis thus relies on multiple factors, including fungal culture tests, radiology scans and patient clinical presentation and risk.

To help overcome this bottleneck, White and colleagues have been putting together an algorithm to combine these factors into a tool that gives probability of fungal disease. They have also developed molecular assays to identify fungal infections through genotype.

Using quantitative polymerase chain reaction (qPCR), tests can quickly identify telltale fungal DNA in a sample and detect known mutations associated with antifungal resistance, particularly to azoles^​27​. A more comprehensive approach using next-generation sequencing can screen fungal DNA for known resistance mutations across multiple genes and identify new mutations that may also contribute to resistance.

 “Unfortunately, there is still an archaic mindset about fungal disease that says we do not have to worry about it,” says White. “But to get ahead, we need to understand the amount of disease that is being caused by fungi, and the extremely serious consequences of fungal disease need to be recognised and accepted.”